Solid cancers (malignant tumors) are named e.g. “breast” cancer and “large intestine” cancer depending on the sites of onset and metastasis; however, cancer cells, the cause of a disease, are various. Cancers in one tissue are variously classified with the development of molecular biology, and correlation with the effect of an anticancer drug has been studied.
Breast cancer is a cancer in which mammary gland lobular epithelium secreting milk, or mammary duct epithelium which is a passage to mammary duct becomes malignant, and is the most frequent malignant tumor among Japanese women in recent years. Various genes including BRCA1 and BRCA2 are suggested to be involved in breast cancer, and classified into various subtypes by their expression levels.
There are, for example, classification by the expression levels of estrogen receptor (ER) and progesterone receptor (PgR) related to the estrogen dependency of cancer cell growth, and classification by the expression level of HumanEGFR-Related2 (HER2), a receptor tyrosine kinase which is also a cancer gene.
Antiestrogen drugs (such as tamoxifen) are effective for cancers in which the expression levels of estrogen receptor (ER) and progesterone receptor (PgR) are higher, and trastuzumab, an anti-HER2 monoclonal antibody, for example is effective for cancers in which the expression of HER2 is higher, and they are administered to patients.
Accordingly, breast cancer has a good pathological complete response (pCR) rate when the expression levels of estrogen receptor (ER) and progesterone receptor (PgR) are higher and the expression of HER2 is higher. That is, the pCR rate is better in
1: (ER·PgR-positive, HER2-positive)=(sensitive to antiestrogen drugs, sensitive to anti-HER2 monoclonal antibodies) (luminal B (HER2-positive) type),
2: (ER·PgR-positive, HER2-negative)=(sensitive to antiestrogen drugs, insensitive to anti-HER2 monoclonal antibodies) (luminal A type or luminal B (HER2-negative) type), or
3: (ER·PgR-negative, HER2-positive)=(insensitive to antiestrogen drugs, sensitive to anti-HER2 monoclonal antibodies) (non-luminal type).
HER2 and ER are called predictive factors because of a relation to the effect of therapy, and are clinically applied (Non-patent Literature 10). A factor whose presence or absence is correlated with prognosis is called a prognostic factor. PgR is currently thought to be a prognostic factor. It is often to use mainly an immunohistochemical method (IHC method) for tumor tissue samples to detect a predictive factor. Either a method in which both the staining intensity of tumor cells and the ratio of stained cells are considered (such as AllredScore) or a method in which the staining intensity is not evaluated and only the ratio of stained tumor cells is used for determination (such as J-Score) is used.
HER2 is generally diagnosed by an IHC method, and determined as negative when the result is 0 or 1+, and as positive for 3+. When the result is 2+, the presence or absence of amplification is examined by a FISH method (Fluorescence in situ hybridization), and HER2 is determined as positive when there is amplification and as negative when there is not amplification.
ER is determined as positive when AllredScore is 3 to 8, and it is often to set 10% as a cutoff value when determining ER by the ratio of stained cells; however, there is also an opinion that when the cells are present even at 1%, ER should be determined as positive. In any case, when a fixed cutoff value is set and these genes (predictive factors) are determined as positive, these can be effective guidelines for therapy regimens.
However, it is reported that there is triple negative breast cancer (TNBC) (ER-negative, PgR-negative, HER2-negative), in which the expression of all the ER, PgR and HER2 is not observed and to which the above antiestrogen drugs and HER2 monoclonal antibody are not effective as an anticancer drug, in breast cancers.
Triple negative breast cancer (TNBC) is present at 11 to 23% in all breast cancers, and is currently thought to have poor prognosis. The effects of not only the above target-specific drugs but also other general anticancer drugs vary depending on patients, and it is suggested to require further subtyping (Non-patent Literatures 7 and 8).
It is shown that TNBC can be currently classified by gene profiles into at least the following 6 subtypes in academics:
Two basal-like (BL1 and BL2) subtypes (with high expression of cell cycle-related genes and DNA damage response genes);
Immunomodulatory (IM) subtype (with high expression of genes related to immune reactions);
Mesenchymal (M) subtype (with high expression of genes related to TGF-β and Wnt/β-catenin signaling);
Mesenchymal-stem like (MSL) subtype (with expression of M type+high expression of stem cell-related genes); and
Luminal androgen receptor (LAR) subtype (with high expression of AR and luminal-related genes).
However, it is difficult to correlate such gene expression profiles with the drug sensitivity of cancer cells, and basic studies have been still advanced (Patent Literatures 1, 2 and 3; Non-patent Literatures 1, 2 and 9).